The main goal of the Program Grant is to obtain a deeper understanding of the immunobiology of nonmyeloablative allogeneic hematopoietic cell transplantation with or without concomitant organ transplantation such that a state of immune tolerance can be achieved. The Program Project has one clinical project (Project 1) (S. Strober, Leader) that will attempt to induce immune tolerance to HLA haplotype matched combined kidney and hematopoietic cell transplants by altering the balance of residual host T cells with the non-myeloablative conditioning regimen of total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (ATG). Project 2, (J. Shizuru, Leader), will perform new preclinical studies of TLI and ATG to investigate the cellular basis by which this conditioning regimen promotes the engraftment of hematopoietic stem cells. Project 3 (R. S. Negrin, Leader) will perform additional preclinical studies that elucidate the function of donor CD4+CD25+ Treg cells and show how they can be used more effectively to prevent GVHD while maintaining graft anti-tumor (GVT) activity. The interactions between donor T cells and subsets of host antigen presenting cells defined in Projects 1 and 4 will be determined also. Project 4 (E. Engleman, Leader) studies the mechanisms by which different subsets of host antigen presenting cells including dendritic cells activate and interact with different subsets of donor T cells including CD4+CD25+ regulatory T cells and Thi and Th2 conventional T cells. Core A (S. Strober, Leader) will provide statistical and administrative assistance to all Projects. Core B (R. Lowsky, Leader) will perform all human donor cell collections and cell purifications for purposes of transplantation into patients in Project 1, and will provide whole or purified subsets of peripheral blood mononuclear cells (PBMCs) from recipients, donors and controls to Projects 1, 2, and 4 and to Core C. Core C (E. Engleman, Leader) will provide immune monitoring assays of lymphocyte function as well as gene microarray assays to Projects 1, 2, and 4. RELEVANCE: The results of the proposed studies are expected to allow for the discontinuation of immunosuppressive drugs in kidney transplant patients, and avoid cumulative drug side effects. The results are also expected to reduce the risk of graft versus host disease in patients given hematopoietic cell transplants to treat leukemia and lymphoma. (End of Abstract)